Diels−Alder chemistry is a well-explored avenue for the synthesis of bioactive materials; however, its potential applications have recently expanded following the development of reactions that can be performed in buffered aqueous environments at low temperatures, including fulvene−maleimide [4 + 2] cycloadditions. In this study, we synthesized two novel amine-reactive fulvene linkers to demonstrate the application of this chemistry for generating mass spectrometry-cleavable labels ("mass tags"), which can be used for the labeling and detection of proteins. Successful conjugation of these linkers to maleimidelabeled peptides was observed at low temperatures in phosphatebuffered saline, allowing the non-destructive modification of proteins with such mass tags. The labile nature of fulvene−maleimide adducts in the gas phase also makes them suitable for both matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) mass spectrometric analysis. Unlike previous examples of MALDI mass tags, we show that fulvene−maleimide cycloaddition adducts fragment predictably upon gas-phase activation without the need for bulky photocleavable groups. Further exploration of this chemistry could therefore lead to new approaches for mass spectrometry-based bioassays.
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